Heart failure is a syndrome in which abnormalities in cardiac function, disturbances in myocardial bioenergetics, abnormalities in neural and humoral circulatory control and disturbances in the peripheral vascular tone all contribute to the clinical symptomatology and to the progression of the disorder. This program project explores each of the abnormalities in various experimental models as well as in patients with heart failure to help define mechanisms that contribute to the physiologic abnormality characteristic of the process. Advanced technologies are key to many of the experimental protocols. The use of ultrasonic crystals to quantitate ventricular function in the dog is critical to two of the projects, the use of NMR spectroscopy to assess myocardial energetics is a key component of three of the projects, measurements of circulating hormones activated in heart failure are utilized in three projects, microsphere blood flow in the myocardium is a key hemodynamic variable in two of the projects, and measurements of norepinephrine kinetics, forearm blood flow and forearm arterial compliance are key features of the clinical proposal. These studies lean heavy on pharmacological intervention in order to explore mechanisms by directly stimulating or interfering with known pharmacologic receptors. Interaction among the investigators includes the sharing of technology, sharing of experimental models, and the rapid incorporation of advances from one project into experimental design of other projects. The long-term goal of these studies is to gain insight into the interactive nature of all of these pathophysiologic events that appear to be contributory to the syndrome of heart failure with the hope that an understanding of mechanism will lead to improvements in diagnostic acumen and therapeutic success.